Markov, M.

Yakimov, G.

Zhelyazkov, D.

English

Varna Medical University Press: Journals

ON T H E A N T I A R R H Y T H M I C A C T I V I T Y O F I S O T E O L I N E (1ST) M. M a r k o v , D . Z h e l y a z k o v , G . Y a k i m o v K e y - w o r d s : i so teo l ine - a r r h y t h m i a - g l auc inc - therapy The use of various experimental models of arrhythmias varying in pathogenetical details from each other enables the relatively adequate evaluation of substances which are potential candidates for medicinal dmgs designated for treatment of cardiac arrhythmias. The former ex­perimental practice (10 ) has proved the reliability of this approach in looking for and creating of new means preventing or correcting cardiac rhythmic disorders. Based on literature data about the pathogenesis of single kinds of experimental arrhythmias they can be conditionally divi­ded into two main groups: 1. Arrhythmias in the genesis of which a cardinal role is played by receptor and probably pre-receptor adrenergic mechanisms. Adrenalin, strophantin and barium arrhythmias belong to this category. 2. Arrhythmias resulting from disturbed post-receptor in­tracellular mechanisms. Both calcium and aconitine arrhythmias can be ranked to a great extent in this group (3) . This classification of models of arrhythmias used by us is close to V . Wil­liams' one (11 ) and provides a good basis for understanding the mechanisms of antiarrhythmic means. The purpose of the present work is to study by using some experimental models of arrhy­thmias selected from these two groups mentioned the antiarrhythmic activity o f isoteoline (1ST) obtained by a previously described method (1 ) and to compare it with that of glaucine, being its derivative. Material and Methods Experiments were carried out on 32 white male rats of Wistar breed with mean body weight of 253 ± 14 g narcotized wi th thiopental-sodium at dosis of 40 mg/kg i.p.; 8 non-narcotized rabbits with mean body weight ^ ' 2 6 0 0 ± 0.600 g, and 6 guinea-pigs narcoitzed with uretane at dosis of 1.2 g/kg i.p. (mean body • 'ight o f 620 ± 70 g). Rhythmic disorders were registered on 12-channel polyphysiograph "Ga l i l e e " or on monochannel electro-cardiograph "Cardiomet". The following models of arrhythmia were used: induced by adrenalin in rats (after I . Gilbert et al . , 1959); induced by barium dichloride in non-narcoitzed rabbits (after L . Szekeres and P. Papp, 1971); by strophantin К in guinea-pigs (after H. Schmitt et Mme I I . Schmitt, 1960); by calcium dichloride in rats (after M. Malinov et al. , 1955), and by aconitine in rats (after M. Fe-kete and I . Dorsy, 1964). Results and Discussion The negative chronotropic effect of 1ST (2 ) that is previously reported presents a principle precondition for a possible antiarrhythmic activity. This was our initial reason to study the po­tential antiarrhythmic activity of 1ST in these 5 models of arrhythmia mentioned different not only concerning the inducing agent but also concerning the mechanisms of their development. The adrenalin arrhythmia in rats induced by i.v. administration of 60 mkg/kg adrenalin is characterized by rapid transitoriness, poly topic ventricular extrasystoles, and sinus bradycardia. 1ST injection precedes adrenalin one by 2 min with protection purpose. 1ST exerts a manifested O n the a n t i a r r h y t h m i c . 29 and long-lasting (more than 60 min) protective effect concerning this kind of arrhythmia at doses of 0.5, 1.0 and 5.0 mg/kg i.v. (fig. 1). The barium arrhythmia in non-narcotized rabbits is induced by injection of 2% barium di-'oride solution at doses of 2 and 4 mg/kg in the auricular marginal vein. Rhythmic disorders Time in min -70 ^ -20 Z -30 <*> * -40 SO I -60 о ^ -70 -80 F i g . 1 . Dependence o f 1 S T pro t ec t i v e e f f ec t on i t s dos is i n ad r ena l i n a r r h y t h m i a in ra ts . H e a r t rate changes caused by adrena l in p r i o r to ( 1 ) a n d a f ter 1 S T a d m i n i s t r a t i o n are f o l l owed-up . 1 - A d r e n a l i n 6 0 ;Ug/kg i v . ; 2 - A d r e n a l i n after 0 .5 mg/kg i v . 1 S T ; 3 - A d r e n a l i n a f ter 1 mg/kg L v . 1 S T ; 4 - A d r e n a l i n a f ter 5 mg/kg L V . 1 S T followed-up for 30 min occur usually on the 1 5 m - 3 0 t h sec after injection of arrhythmogenic agent and are characterized by polymorphous ventricular extrasystoles, bigeminy-type, sinus bradycardia and AV-block manifestations. Both 1ST and glaucine are applied at doses of 0.5 and 2.0 mg/kg i.v. 5 min prior to ( in a prophylactic regimen) and on the 2n^ min after barium dichloride injection ( in a therapeutic one). The results obtained show that 1ST at these doses exerts an expressed antiarrhythmic effect concerning barium arrhythmia in rabbits, both pro­tectively and therapeutically applied. However, glaucine does not possess any antiarrhythmic activity with this model of arrhythmia. Strophantin arrhythmia induced in guinea pigs by i.v. injection of 200 mkg/kg strophantin К is characterized by delayed A V conduction, ventricular tachycardia and extras} stoles. Protecti-% vely, 1ST was applied at dosis of 0.5 mg/kg 5 min prior to, or on the 1 s t min after strophantin induction with therapeutic purpose. I t is found out that 1ST has a good protective effect on arrhythmia but no therapeutic one. Calcium arrhythmia in rats is induced by i.v. injection of calcium dichloride as 10% solution at dosis of 120 mg/kg. Sti l l on the 15th s e c a f t e r introduction of the agent a severe arrhythmia sets in manifested with polytopic ectopic foci and ventricular fibrillation resulting in lethal outcome for 2 - 4 min. 1ST is used with protective purpose only, i.e. 5 min prior to calcium di­chloride injection, at doses of 5 and 10 mg/kg i.v. It is established mat 1ST does not demonstra­te any antiarrhythmic activity. Aconitine arrhythmia in rats is induced by slow i.v. injection of aconitine at dosis of 60 mg/ 30 M. Markov, D. Zhe lyazkov, G . Y a k i m o v kg. To this purpose aconitine solution in concentration of 0.2% is ex tempore prepared by add­ing of 2 drops 0.1 nHCl to distilled water and then stored at dark and cool conditions because of its light sensitivity. Usually, on the 30th sec after aconitine application severe disorders of cardiac rhythm can be observed characterized by polytopic ventricular extrasystoles passing into paroxysmal tachycardia, atrial fibrillation and flickering, and lethal outcome (heart arrest in diastole) in 100 per cent of the cases on 1 0 m —. 1 5 . m m i n . 1ST can not influence upon rhy­thmic disturbances when it is applied at doses of 5 and 10 mg/kg i."v. neither in a prophylactical, nor in a therapeutical regimen. These results show that 1ST applied at relatively low doses (0.5 — 2.0 mg/kg) manfiests its antiarrhythmic activity in cases o f adrenalin, barium and strophantin arrhythmias. However, it can not influence calcium and aconitine arrhythmias even at doses of 5.0 - 10.0 mg/kg i.v. These data are of interest mainly because they reveal that 1ST is a substance acting not only prophylactically but also therapeutically in cases of rhythmic disturbances of heart activity with stress genesis. Second, they indicate that it wil l be useful in prophylaxis o f arrhythmias induced by cardiac glycosides. In this respect its activity is analogous to that of other well-known central D i -dopaminergic agonists such as bromocryptin, apomorphin, piribecyl, etc., which realize their protective effect by means of activation of central dopaminergic mechanisms at area postrema level resulting in reduction of peripheral sympathetic activity (4 ) . A t last, the data showing that 1ST is ineffective in aconitine and calcium arrhythmias where, as mentioned, sympathetic mechanisms are not pathogenetically involved, also point that 1ST realizes most ef­fects of its rich pharmacology principally by means of central reduction of peripheral sympa­thetic activity. R E F E R E N C E S 1. Ж е л я 3 к о в , Д., Н. М о л л о в, М. М а р к о в, С. Ф и л и п о в, Н. Г е о р г и е в, М. С а в о-в а , М. М а р к о в а , А. М а л е е в а , Н. Т ъ р к о л е в . Авт. свидет. № 34200 , ИНРА, 1983. - 2. Ж е¬л я з к о в, Д., М. М а р к о в , Н. Г е о р г и е в , М. Т а с к о в . Експерим. мед. и морфол., 1965 , № 1, 1 3 - 1 9 . - 3. С a i 11 а г d, С , J . L u \%.Meth. Find. Experim. Clin. Pharmacol, 2 , 1 9 8 0 , N o 5, 2 2 5 - 2 5 2 . -4. F a 1 k, R . , R. D e s i l v a , B. L о w n. Cardiovasc. Res., 15, 1 9 8 1 , N o 5 , 1 7 5 - 1 8 0 . - 5 . F е k е t e , N. . J . D o r sy.Med. Experim. (Basel), 10, 1964 , N o 2, 9 3 - 1 0 2 . - 6. G i 1 b e r t, J . , G . L a n g о, C . B r o c k s , Circul. Res., 7, 1 9 5 9 , 4 1 7 . - 7. N е 1 k о, C , R. N. G i U i c, J. Pharmacol. Experim. Ther., 2 0 7 , 1 9 7 8 , N o 2, 2 6 5 - 2 7 0 . - 8. M a 1 i n о v, M., F . В a 11 e, D. M a 1 a m и d. Arch. Interna. Pharmacodyn. Ther., 102 , 1 9 5 5 , 266. - 9. S с h m i t t, H . , M m е H. S с h m i 1 1 Arch. Internal. Pharmacodyn. Ther., 127, 1960 , 1 6 3 - 1 7 9 . - 10. S z е k е r e , L . , J . P a p p . I n : Expe r imenta l cardiac ar rhythmias and ant iar rhythmic drugs. Budapest, Akademia K iado , 1 9 7 1 , 4 4 8 . - 1 1 . W i 11 i a m s, V . In : S y m p . on cardiac arrhythmias. Denmark , 1 9 7 0 , 4 4 9 - 5 0 1 . К ВОПРОСУ ОБ АНТИАРИТМИЧЕСКОЙ АКТИВНОСТИ И З О Т Е О Л И Н А (ИЗТ ) М.Марков, Д. Желязков, Г. Якимов Р Е З Ю М Е Исследована антиаритмическая активность изотеолина при нескольких экспериментальных мо ­делях сердечной аритмии: адреналиновая сердечная аритмия на крысах, бариевая на ненаркотизи-рованных кроликах , строфантиновая на морских свинках и аконитовая и кальциевая на крысах. Нарушения ритма сердца регистрировались при помощи 12-канального полифизиографа „ Г а л л и -л е о " или при помощи одноканального электрокардиографа „Кардиомат " . Полученные результаты показывают, что изотеолин проявляет антиаритмическую активность по отношению к адреналиновой, бариевой и строфантиновой типов аритмии. В то же время не отмеча­ется существенного влияния изотеолина на аконитовую и кальциевую аритмии. Авторы считают, что антиаритмическая активность изотеолина, установленная при указанных выше моделях экспериментальных моделях сердечной аритмии, связана, по всей вероятности, с понижением симпатической периферической активности, которая реализуется центрально. * 

ON THE ANTIARRHYTHMIC ACTIVITY OF ISOTEOLINE (IST)

https://journals.mu-varna.bg/index.php/ssm/article/download/2984/2441

ON THE ANTIARRHYTHMIC ACTIVITY OF ISOTEOLINE (IST)

Abstract

Similar works

Full text

Available Versions

Varna Medical University Press: Journals